Project Summary/Abstract Despite major advances in treatment and prevention of HIV infection, the HIV/AIDS pandemic continues to cause tremendous morbidity and mortality. Of the 36.7 million people living with HIV worldwide, only 57% are receiving antiretroviral therapy. One million people died from AIDS-related illness in 2016, and nearly two million are newly infected with HIV each year. The HIV burden is highest in parts of the world that face the additional challenge of constrained resources. HIV testing and treatment guidelines have continually evolved, capturing the benefits associated with improved testing, more effective antiretroviral therapy and lab monitoring, and increasingly effective prevention interventions. It is clear that the pandemic could be better controlled using existing tools. What remains unclear, however, is what specific strategies and overall approach would be most effective for specific populations, given the important reality of budget constraints. This competing continuation proposes to expand upon the Cost-Effectiveness of Preventing AIDS Complications International (CEPAC-I) Model, a computer microsimulation of the natural history, clinical management, outcomes, costs, and cost-effectiveness of HIV treatment. It will identify the testing, treatment, and prevention interventions that provide the most value in terms of decreasing HIV incidence and improving life expectancy with HIV. The CEPAC-I team, made up of a collaboration of leading HIV investigators, is based in the United States, with key collaborators in South Africa, Cte d'lvoire, India, and Brazil. This team will address critical questions around the cost-effectiveness of new interventions for HIV in high-risk populations. The results will inform clinicians, policymakers, and people living with HIV in multiple resource-limited settings. In addition, this proposal includes development of innovative modeling optimization methods to identify the combinations of testing, treatment, and prevention strategies that will have the greatest impact on specific populations in different countries. This proposal has two specific aims: Specific Aim 1: To expand the CEPAC-I microsimulation to address clinical policy questions, focused on key populations, using data from recent clinical trials and implementation research studies. Specific Aim 2: To develop a novel optimization model to determine the combination of HIV care interventions that maximizes survival, or minimizes HIV incidence, in countries with different epidemic characteristics and different resource constraints. In close alignment with the 2018 research priorities of the NIH Office of AIDS Research, the goals of this proposal include reducing the incidence of HIV, investigating next-generation therapies, identifying optimal prevention and treatment responses, and reducing health disparities by improving outcomes in key populations.